Novel substituted(nitrofurylacrylidene)hydrazines with antibacterial properties

ABSTRACT

1. A SUBSTITUTED (NITROFURYL ACRYLIDENE) HYDRAZINE REPRESENTED BY THE FORMULA:   2-(O2N-),5-(6-(NH-CH(-R)-CO)N-NH-N=CH-CH=CH-)-FURAN   IN WHICH N=1 OR 0; G IS A MEMBER OF THE GROUP CONSISTING OF THENOYL, NITROTHENOYL AND CARBOBENZOXY RADICALS; AND R, WHEN N=1 IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND METHYL, BUTYL, ISOBUTYL, $-(2-FUROYL)AMINOBUTYL, BENZYL, HYDROXYMETHYL AND P-HYDROXYBENZYL RADICALS.

United States Patent 3,847,911 NOVEL SUBSTITUTED (NITROFURYLACRYL-IDENE) HYDRAZINES WITH ANTIBACTERIAL PROPERTIES Etienne Szarvasi,Charbonnieres-les-Bains, and Louis Fontaine, Lyon, France, assignors toLipha, Lyonnaise Industrielle Pharmaceutique, Lyon, France No Drawing.Filed Jan. 5, 1972, Ser. No. 215,677 Claims priority,appli7cilifilssFrance, Jan. 7, 1971,

Int. Cl. C09b 23/00 US. Cl. 260-240 A 14 Claims ABSTRACT OF THEDISCLOSURE The present invention relates to substituted(nitrofurylacrylidene) hydrazines, their preparations and theirapplications.

The novel compounds are represented by the general formula in which n=1or O, G is a member of the group formed by the furoyl, thenoyl,nitrothenoyl and carbobenzoxy radicals and R, when n=1, is a member ofthe group formed by hydrogen, the methyl, butyl, isobutyl, -(2- furoyl)aminobutyl, hydroxymethyl, benzyl and p-hydroxybenzyl radicals.

The novel nitrated derivatives are endowed with antibacterialproperties.

The present invention relates to substituted (nitrofurylacrylidene)hydrazines, the processes for the preparation thereof and theapplications thereof. It is also concerned with obtaining initialproducts and intermediate products in the synthesis of novel hydrazines.

The compounds according to the invention can be used in theantibacterial field. Certain nitrofurans are known and used in pharmacyand in the veterinary field, such as particularly the N (2furfurylidene) 3-amino-2-oxazolidone, known under the commercial markFuroxone and the N (2 furfurylidene) 3-amino-hydantoin, at present knownunder the commercial mark Furadoin.

These products used in pharmacy do however have inconveniences, such asan emetic effect.

The novel nitrofurans of the invention, as well as having an appreciableantibacterial activity for a toxicity of the same order as that ofFuroxone and decidedly lower than that of Furadoin, have the very greatadvantage of not being emetic.

The (nitrofurylacrylidene) hydrazines of the invention are representedby the formula:

in which n=1 or 0;

G is a furoyl, thenoyl, nitrothenoxyl or carbobenzoxy radical; and

R, when n=1, hydrogen, methyl, butyl, isobutyl, 6- 2 furoyl)-aminobutyl,benzyl, hydroxymethyl and p-hydroxybenzyl radical.

'ice

It is possible to obtain these novel hydrazines by reaction of5-nitro-2-furyl acrolein with a hydrazine which is represented by theformula G-(NH- ?H0 0 NHNH2 R a in which n, G and R have the samemeanings as in formula I. These hydrazines can be obtained by hotcondensation in organic solvent medium. The present invention is alsoconcerned with novel substituted hydrazides, which can be usedparticularly as intermediaries in the synthesis of the compoundsaccording to formula I, and represented by the formula G-(NH(|3HC O)NHNH:

R n in which n=1 or 0;

G is a furoyl, thenoyl, nitrothenoyl or carbobenzoxy radical, exceptwhen R is hydrogen, a hydroxymethyl or p-hydroxybenzyl radical; and

R is hydrogen, a methyl, butyl, isobutyl, hydroxymethyl,

p-hydrobenzyl, benzyl or furoylbenzyl radical.

These hydrazides can be obtained by reacting the hydrazine with an aminoester of formula:

GNH-(JHCO2C2HB R (III) According to one variant, the process can be usedin the presence of a catalytic quantity of acid, such as acetic acid.

The present invention also relates to certain novel amino esters, whichcan be used particularly as intermediaries in the synthesis ofhydrazides and hydrazines as previously described. These amino estersare represented by the formula:

R (111') in which G is a furoyl radical, when R is a methyl, 6-(2-furoyl) aminobutyl or p hydroxybenzyl radical, a thenoyl radical when Ris hydrogen, a butyl or isobutyl radical, a nitrothenoyl radical when Ris a hydroxymethyl or benzyl radical, or carbobenzoxy when R is anisobutyl radical.

These amino esters of the invention can be obtained by reacting an aminoester of formula H2N?HC OzCzHi R with an acid chloride of formula G-Cl,in which G and R have the same meanings as in formula (III), in thepresence of an alkali agent. According to variants of the invention, thealkali agent is mineral or organic, such as the acid carbonate ofsodium, triethylamine, pyridine.

The novel (nitrofurylacrylidene) hydrazines are distinguished by theirability to inhibit the growth of bacteria. This effect extends togram-positive and gram-negative organisms.

Biological research has made apparent the importance of the nature ofthe protective group G of the general formula I. The effect of thesegroups can be classed in the following order.

man a- Since it has been established to be advantageous to select theheterocyclic carrier of the NO group participating in the formation ofthe Schiff base from the family of furans and thiophenes, the biologicalactivity being completely lost when they are replaced by the isostere;pyrrol, the [N -(5-nitro-2'-thenoyl)-N -(5nitro-2"-furylacrylidene)]-hydrazine and [N -(5'-nitro-2'-thenoylglycyl)-N -(5"-nitro-2"-furyl acrylidene) ]-hydrazine form particularlyoutstanding active principles.

These two products have an activity in vitro which is identical withthat of Furoxone for an equal toxicity. In addition, a particularlyimportant fact is that these active principles are free from any emeticeffect on the dog, even in a strong dose.

The medicaments of the invention have low toxicity, the strongest dosetolerated by mice by oral route being at least 3200 mg./kg.

The results of pharmacological tests are set out in the following tablesI and II.

In table I, the control substance is Furoxone and in table II it isFuradoin.

The antibacterial coeflicients have been determined in vitro in themajority of cases on specific E. Coli strains.

TABLE I LDso, kg. per- Antibacterial orally mice coefiioient (mg) 1 Invitro. 2 On grams positive germs.

TABLE II LDsu, kg. Antibacterial perorally mice Example coeflicient (mg)EXAMPLE 1 p N -[2-thieny1 acetyl]-N [5-nitro-2'-pyrrolylidene]-hydrazine 3.9 g. (mol/40) of (Z-thienyl acetyl) hydrazide are dissolvedin 32 ml. of methanol, whereafter 3.5 g. (mol/ 40) of5-nitro-2-pyrrolaldehyde in 35 ml. of tetrahydrofuran are added. Heatingunder reflux takes place for 5 hours. After cooling, adding ether andthen cooling in the refrigerator, there are obtained:

1st cut: 3.6 g.yellow, M.P.=118-190 C.

2nd cut: 1.7 g.-yellow, M.P.=190192 C.

The yield is 5.3 g., i.e. 76% (theoretical yield=6.95

The 1st cut, after being recrystallised twice from isopropanol and driedat 50 C. under strong vacuum, melts at 192-194 C.

Gravimetric analysis.-Calculated (percent): C, 47.46; H, 3.62; N, 20.13;S, 11.52. Found (percent): C, 47.37; H, 3.65; N, 19.92; S, 11.66.

EXAMPLE 2 N -[N-2-furoyl (i) alanyl]-N-[5"-nitro-2"-furylacrylidene]-hydrazine is 14 4Ou M=346.20

(a) N-Z-furoyl (1 alanine ethyl ester:

CONII-CHCO2C2H5 10 l3 4 23.4 g. (mol/ 5) of (i) alanine ethyl ester aredissolved in ml. of dry benzene. 20.3 g. (mol/5)=20.22 g.) oftriethylamine are added, followed by dropwise addition of 26.1 g.(mol/S) of furoyl chloride. The temperature is raised from 2 to 35 C.and there is a precipitation of crystals of After suction-filtering,washing with water and drying, and also evaporation of the solvent,there is obtained a quantitative yield of 42.2 g. of product ofM.P.=6871 C. After being recrystallised twice (diisopropylether) themelting point is 72-73 C.

Gravimetric analysis.Calculated (percent): C, 56.85; H, 6.20; N, 6.63.Found (percent): C, 56.83; H, 6.19; N, 6.58.

(b) N -[N'-2-furoy1 (i) alanyl]-hydrazide:

21.1 g. (mol/lO) of N-furoyl (i) alanine ethyl ester, 20.2 g.(incl/25:20 g.) of NH NH -98% H 0 and 0.5 ml. of acetic acid are heatedunder reflux for 5 hours.

After evaporation to dryness, the oily residue which is obtained isdispersed under ether and this is solidified. A White product ofM.p.=l20 C. is obtained with a quantitative yield, this product meltingat 132133 C. after being recrystallised twice from isopropanol.

Gravimetric analysis.-Calculated (percent): C, 48.72; H, 5.62; N, 21.31.Found (percent): C, 48.61; H, 5.77; N, 21.17.

(c) N -[N'-2-'furoyl (i) alanyl]-N -[5-nitro-2"-furylacrylidene]-hydrazine: 10 g. (mol/20=9.85 g.) of N -[N'-furoyl (i)alany1]-hydrazide, in ml. of methanol, and 8.4 g. (mol/20=8.35 g.) ofS-nitro-Z-furyl acrolein, in 63 ml. of tetrahydrofuran, are heatedtogether under reflux for one hour. After concentration to half volume,cooling in a refrigerator, suction-filtering, washing with isopropanoland then with ether, 11.8 g. of product are obtained with a yield of80.5% (theoretical yield =14.65 g.), the product having a melting pointof 192- 195 C. (with decomposition). After recrystallisation fromacetone the melting point is 197.5-198.5 C. with decomposition.

Gravimetric analysis.-Calculated (percent): C, 52.02; H, 4.07; N, 16.18.Found (percent): C, 51.96; H, 4.13; N, 16.07.

EXAMPLE 3 N [N'- carb ob enzoxyglycyl] -N[5'-nitro-2-furylacrylidene]-hydrazine 7 g. (mo1/31.8) of N [N'carbobenzoxyglycyl)- hydrazide are dissolved at ambient temperature in80 ml. of methanol. There are then added dropwise 5.3 g. (incl/31. 8) of5-nitro-2-furyl acrolein in 53 m1. of tetrahydrofuran. Heating underreflux takes place for one hour, followed by concentration to halfvolume. A crystallisation is produced, and the formed crystals aresuction-filtered and washed with ether. There are obtained 8.7 g. ofcrystals melting at 159160 C., with a yield of 74.2% (theoreticalyield=11.7 g.). After recrystallisation (methanol) the melting point isunchanged.

Gravimetric analysis.Calculated (percent): C, 54.83; H, 4.33; N, 15.04.Found (percent): C, 54.92; H, 4.38; N, 15.06.

EXAMPLE 4 N [N'-2'-thenoylglycyl] -N [5 "-nitro-2"-fury1acrylidene]-hydrazine i4HizN4 0.5 S Mfl48. 33

(a) Ethyl-N-thenoyl-Z-glycocollate:

T, C gHnN 38 C CO C H LS ONH CHr- 2 2 1 8 4 Method A.To 14.2. g. (mol/7.25) of ethyl glycocollate in solution in 70 ml. of pyridine are addeddropwise 20.2 g. (mo1/7.25) of 2-thiophene carboxylic acid chloride.Agitation takes place for one hour at ambient temperature and then themixture is poured into iced water. Suctionfiltering, 1st cut: 19.4 g.coloured. M.p.=8688 C. The mother liquors, extracted with ethyl acetate,yield a second cut: 6 g. coloured. 'M.p.=8688 C. Yield: 25.4 g.=86.4%(theoretical yield=29.4 g.).

Method B.To a solution of 21.1 g. (mol/ 6.6) of ethyl glycocollatehydrochloride, in 150 m1. of water, containing 25.3 g. (mol/3.3) ofNaHCO there are simultaneously added while stirring well; 24.1 g. (mol/6.6) of Z-thiophene carboxylic acid chloride and 38 ml. of an aqueoussolution containing 12.7 g. (mol/ 6.6) of NaHCO The time taken for theaddition is minutes. Heating at 50 C. takes place for one hour. Thesolid is precipitated on completing the addition. Aftersuction-filtering, washing with water, there are obtained 25.5 g.=79%(theoretical yield: 32.2 g.) of coloured product, -M.P.=8890 C.

After recrystallisation (diisopropyl ether+ethyl acetate), a whiteproduct of M.P. 90-90.5 C. is obtained.

Gravimetric analysis.Calculated (percent): C, 50.70; H, 5.20; N, 6.57;S, 15.04. Found (percent): C, 50.72; H, 5.23; N, 6.54; S, 14.99.

vNH, 3,400 cm."

vCH=CH (thiophene), 3,120 cm.- vCO (ester), 1,740 cm.-

wCO (conjugated amide), 1,650 cm."

(b) N -[N'- '-thenoylglycyl]-hydrazide:

21.3 g. (mol/ 10) of ethyl =N-2-then0yl glycocollate, 20 g. (mol/2.5=20g.) of 98% hydrazine, 30 ml. of isopropanol and 0.4 ml. of acetic acidare mixed. A heating is produced, followed by crystallisation. Thecrystals are left at ambient temperature for a few hours and then in arefrigerator. After suction-filtering, washing with ether, there areobtained: 19.9 g.=97% (theoretical yield: 19.9 g.) of solid melting at176-177 C. After recrystallisation (water) and drying at C. undervacuum, M.P.=178- 179 C.

Gravimelric analysis-Calculated (percent): C, 42.20; H, 4.53; N, 21.10;S, 16.10. Found (percent): C, 42.29; H, 4.60; N, 21.05; S, 16.16.

vNH, 3,300 cm."

vCO (conjugated), 1,6301,650 emf VCO, 1,670 cm."

vCH=CH (thiophene), 3,080 cm.-

11C=C (thiophene), 855 cm.- -1.030 cm.- 1,06O cm.-

(c) N -[N'-2-thenoylglycol] -N [5"-nitro 2" furylacrylidene]-hydrazine:8 g. (mol/25=7.95 g.) of N -[N- 2'-thenoylglycyl]-hydrazide aredissolved at 60 C. in 200 ml. of ethylene glycol. At a temperature of 50C., 6.8 g. (mol/25) of 5-nitro-2-furyl acrolein in 68 ml. oftetrahydrofuran are introduced. crystallisation is produced a fewminutes after the addition. Heating takes place at 50 C. for 30 minutes.After suction-filtering and washing with ether, there are isolated 13.8g. of solid with a melting point of 233-234 C. (with decomposition) andwith a yield of 99.3% (theoretical yield=13.9 g.). Afterrecrystallisation from a mixture of dimethyl formamide and ether, themelting point is 233 C. (with decomposition).

Gravimetric analysz's.-C-alculated (percent): C, 48.27; H, 3.47; N,16.08; S, 9.20. Found (percent): C, 48.19; H, 3.43; N, 15.98; S, 9.30.

vNH, 3,380 emr v00, 1,690 cm.-

1 00 conjugated, 1,645 cm.- vC-NO2, 1,510 and 1,550 emr WI, 1,020 cm.-

C 14H11N5 O 7 S (a) N [5 '-nitro-2-thenoylglycyl] -hydrazide:

1st cut: 11.5 g., yellow, M.P. =186-187 C. 2nd cut: 4.8 g., yellow,M.P.=189.5190 C.

The yield is 16.3 g.-=80.5% (theoretical yield: 20 g.). After beingrecrystallisation twice (water),

M.:P.=190.5191 C.

Gravimetric analysis.-Calculated (percent): C, 34.42; H, 3.30; N, 22.94;S, 13.13. Found (percent): C, 34.55; H, 3.34; N, 22.90; S, 13.25.

z NH, 3.330 cm.-

vCO, 1,680 Crn."

vCO conjugated, 1,640 cm. VNOZ, 1,580 cm.-

(b) N -['-nitro-2'-thenoylglycyl]-N -[5" nitro 2"- 5furylacrylidene]-hydrazine: At a temperature of 60 C., 6.1 g. (mol/40)of N -[nitro-2-thenoylglycyl]-hydrazide are dissolved in 200 ml. ofethylene glycol. At the same temperature, 4.2 g. (mol/ 40) of5-nitro-2-fury1 acrolein in 42 ml. of tetrahydrofuran are introducedinto the solution. Heating takes place for one hour at 60 C. Aprecipitation of red crystals is observed after cooling. (In certaincases, after heating for half an hour.) After filtering with suction andwashing with water, there are obtained 8.1 g., yield=82.6% (theoreticalyield: 9.84% g.) of an orange product, M.P.=217218 C.

After recrystallisation (8.1 g. in 875 ml. of ethyl acetate) and dryingto constant weight at 140 C. under a strong vacuum, the melting point isZZZ-224 C. (with decomposition).

Gravimetric anaIysis.-Calculated (percent): C, 42.76; H, 2.81; N, 17.81;S, 8.15. Found (percent): C, 42.70; H, 3.04; N, 17.78; S, 8.09.

IR analysis:

1,720 cmr (C0 of the enolised hydrazidel J, 3,100 cm.-

14.2 g. (mol/ 10) of N -(2'-thenoyl)-hydrazide in crude form aredissolved in 140 ml. of methanol. 16.7 g. (mol/ 10) of 5-nitro-2-furylacrolein in 167 ml. of tetrahydrofuran are added dropwise thereto. Thesolution is heated under reflux for one hour. Crystallisation isobserved 5 minutes after completing the addition. After cooling, thereis obtained a first cut of 16.9 g. of yellow crystals, M.P.=219220 (withdecomposition).

After concentrating the mother liquors, there are obtained at second cutof 1.1 g. (yellow), M.P.=219-220 C. (with decomposition) and a third cutof 3.5 g. (brown) of M.P.=212-213 C. (with decomposition). Yield: 21.5g.=72.6% (theoretical yield: 29.1 g.).

After recrystallisation (alcohol+dimethyl formamide at 80 C.),M.P.=219220 C. (with decomposition).

Gravimetric analysis.Calculated (percent): C, 49.48; H, 3.11; N, 14.43;S, 11.01. Found (percent): C, 49.50; H, 3.14; N, 14.36; S, 11.12.

vNH, 3,280 cm.- vNO 1,540 cm.- z/CO (conjugated), 1,650 cm.

8 EXAMPLE 7 (a) N,N-2'-difuroyl lysine ethyl ester:

i l M=3(i2. 38 NHCO 24.7 g. (mol./10) of lysine dihydrochloride ethylester are dissolved in 200 ml. of water containing 25.4 g. (mol/3.3) ofNaNcO While stirring vigorously, there are simultaneously added: 26 g.(mol/5) of furoyl chloride and 50 ml. of an aqueous solution of 16.8 g.(mol/S) of NaHCO The addition lasts 20 minutes. Heating to 50 C. takesplace for one hour, followed by extraction with ethyl acetate andevaporation to dryness, the oily residue which is obtained slowlysolidifying. The yield is 22.9 g.=63% (theoretical yield: 36.2 g.) as awhite solid of M.P.=l01102 C.

Analysis.--Calculated (percent): C, 59.65; H, 6.12; N, 7.73. Found(percent): C, 59.70; H, 6.16; N, 7.85.

vNH (large, 3,300 em.-

1100 ester, 1,740 cm.-

vCO amide, 1,650 cm.-

vCH=CH (furan), 3,0603,120 cmr 16.1 g. (mol/ZO) of N,N-2-difur0yl (1:)lysine ethyl ester, in solution in isopropanol, 10.2 g. (mol/5=10 g.) ofNH NH -98% H 0 and 0.5 ml. of acetic acid are heated for 5 hours. Thesolution is evaporated to dryness and the residue is dispersed underether, and there are obtained 16 g., yield=92% (theoretical yield 17.35g.) of a white product melting at 158 C. After recrystallisation(ethanol), the melting point=161162. C.

Analysis.Calculated (percent): C, 55.17; H, 5.78; N, 16.08. Found(percent): C, 55.12; H, 5.80; N, 16.04.

same conditions, a melting point=212-213 C. is reached.Analysis.-Calculatecl (percent): C, 55.52; H, 4.66; N, 14.08. Found(percent): C, 55.45; H, 4.63; N, 14.17.

vNH, 3,380 cm.- VCH: l 2,940 cmr vHC=CH, 3,120 cm.- -1,020 cm.-

I vCO (enolised hydrazide C=N), 1,700 cm.- ;1,650 cm: (comugated) vNOz,1,550 cm.

EXAMPLE 8 N -[car-bobenzoxy (i) leucyl]-N -[5-nitro 2' furylacrylidene]-hydrazine 5 CH; CH; CarHuNeOs M=428A3 (a) N-(i) carbobenzoxy (i)leucine ethyl ester:

@CHRO C ONH-CH-C OgCzHs CreHzaNOt H M=293.34 Cfia CHt Chromatography invapour phase reveals the presence of 20% of volatile impurities.

,uNH, 3.350 cm." ,uCO (large), 1,730 cm.-

(b) N-carbobenzoxy (i) leucyl hydrazide:

29.3 g. (mol/ of N-carbobenzoxy (i) leucine ethyl ester, 320 ml. ofethanol, 204 g. (mo1/2.5=20 g.) of 98% hydrazine hydrate and 0.5 ml. ofacetic acid are left at ambient temperature for 48 hours and thenevaporated to dryness. The residue is washed with water and extractedwith ether. [After evaporation of the ether, an oil is left which isdried under strong vacuum. The yield is 12.3 -g.=44.2% (theoreticalyield: 27.9 g.) of a product which melts at 104-105 C. Afterrecrystallisation (propylene oxide-heptane [2:1], M.P.=105108 C.

This product is not analytically pure and it is used as such.

,uNH 3,2403,340 cm. CH=CH (benzene), 3,050 cm.- uCO (amide), 1,650 cm.-CO (Cbo), 1,730 cm."

(c) N -[carbobenzoxy (i) leucy1]-N [S-nitro 2'-furylacrylidene]-hydrazine: To 14 g. (m0l/20=13.96 g.) of carbobenzoxy(i) leucyl hydrazide in 80 m1. of methanol are added 8.4 g. (mol/ 20) of5-nitro-2-furyl acrolein in 84 ml. of tetrahydrofuran. crystallisationis produced before the addition is completed. Heating under reflux takesplace for one hour, followed by concentration to half volume. At ambienttemperature, ether is added, cooling takes place and there are obtained10.9 g. [yield=88% (theoretical yield: 12.4 g.)] of yellow solid,M.P.=142 145 C.

After recrystallisation (ethanol) M.P.=145.5-146 C.

Analysis.Calculatcd (percent): C, 58.87; H, 5.64; N, 13.08. Found(percent): C, 58.75; H, 5.71; N, 13.12.

[.LNH, 3,320 cm.- CO, 1,690 cm.- NO 1,520-1,550 cm.-

EXAMPLE 9 N [N'- (2'-thenoyl) i leucyl] -N [5"-nitro-2"-furylacrylidene1-hydrazine CH3 CH3 (a) N-(Z-thenoyl) (i)leucine ethyl ester:

CHa-CH-CH:

I OH; CONE-CH-C 0202115 B M=260. 34

Method A.Starting from the free amino ester. Following the conditions ofExample 4, with a yield of 67.6%, a product is obtained which distils,B.P. =133-136 C and then is solidified, M.P.=6264 C.

Method B. Starting from the hydrochloride (i) leucine ethyl ester.Following the conditions of Exampe 4, with a yield of 89.4%, there isobtained a white solid of M.P. =6667 C.; the product distils, B.P. =135-137 C.

Chromatography in vapour phase:

V.P.C. (column=S.E. 30; T=215 C.; H =50 ml./min.):

purity: vNH, 3,300 cm.- vCH=CH (thiophene), 3,100 cm." vCO, 1,720 cm.-

(b) N -[N'-(2-thenoyl) (i) leucyl]-hydrazide:

CH3CH CH3 C11H17N3O2 S vNH, 3,200 cm."

11CH=CH (thiophene), 3,120 cm.- vCO, 1,660 cm.

vCN, 1,370 cm."

(c) N -[N'-(2'-thenoyl) (1:) 1eucyl]-N -[(5-nitro-2"-furyl)-acrylide-ne]-hyd.razine: Following the conditions of Example 8and starting with 6.4 g. (mol/40-=6.38 g.) of N -[N'-(2-thenoyl) (i)leucyl]-hydrazide. After heating under reflux for 2 hours, concentrationto half volume, adding ether and crystallising at ambient temperature,

11 there is obtained a first cut of 5.5 g. of a yellow solid,M.P.=189190 C., and a second cut of 2.7 g. of yellow solid, M.P.=177-179C.

The second cut, recrystallised from methanol, yields 1.3 g. of product,M.P.=193-194 C. Yield 6.8 g.= 67.5% (theoretical yield: 10.1 g.). Afterrecrystallisation from methanol, M.P.=194.5195 C.

Analysis.-Calculated (percent): C, 53.46; H, 4.98; N, 13.86; S, 7.92.Found (percent): C, 53.50; H, 5.01; N, 13.79; S, 8.00.

vNH, 3,340 cm? 1 vCO (conjugated), 1,640 cmf vCO, 1,690 cm.-

VNOZ, 1,520-1,540 cm.

EXAMPLE l N -[N'-carbobenzoxy (i) seryl]-N-[5'-nitro-2'-furylacrylidene1-hydrazine:

HIGH

g. (mol/ of N-carbobenzoxy (i) seryl hydrazine are dissolved in 200 ml.of tepid methanol. 6.7 g. (mol/ 25 of 5-nitro-2-furyl acrolein in 51 ml.of tetrahydrofuran are added at a temperature of 50 C. After heatingunder reflux for 2 hours, concentration to a third of the initialvolume, addition of ether and after one night in the refrigerator, thereare obtained 10.8 g.=67.5% (theoretical yield=16 g.) of a productmelting at 150-151" C. After recrystallisation (ethanol), M.P.=151152 C.

Analysis.Calculated (percent): C, 53.73; H, 4.50; N, 13.93. Found(percent): C, 53.90; H, 4.67; N, 13.98.

vNI-I, 3,420 cm."

- vCO, 1,700l,730 cm.-

vNO 1,560 cm.-

EXAMPLE 11 N [5 nitro-2-thenoyl]-N -[5"-nitro-2"-furylacryli dene]-hydrazine C12Ha 40aS (a) Ethyl-5-nitro-2-thiophene carboxylate:

17.4 g. (mol/10=17.31 g.) of S-nitrothiophene carboxylic acid aredissolved in 85 ml. of absolute ethanol. A stream of gaseoushydrochloric acid is caused to enter the boiling solution to the pointof saturation, and for 5 hours. Evaporation to dryness takes place andthen the solid residue is washed with a sodium bicarbonate solution. Itis suction-filtered and washed with water. After drying, there areobtained 17.7 g. of a yellow product with a melting point of 63-65 C.and the yield is 88% (theoretical yield=88% The N-(5-nitro-2'-thenoyl)-hydrazide is prepared by reacting hydrazine withethyl 5-nitro-2-thiophene carboxylate.

(b) 6.3 g. (mol/=6.5 g.) of N -[5'-nitro-2-theonyl]- hydrazide aredissolved in 100 ml. of dry tetrahydrofuran. 5.6 g. (mol/30=5.55 g.) of5-nitro-2-furyl acrolein in 56 ml. of tetrahydrofuran are added. Heatingunder reflux takes place for one hour and, 25 minutes after starting theheating, the crystallisation commences; the crystals aresuction-filtered, washed with ether and dried. There are obtained 7.9 g.(yield 70%theoretical yield=11.2 g.) of a yellow solid of M.P.=235236 C.

Recrystallisation (tepid dimethyl formarnide-l-ether) leaves the meltingpoint unchanged.

1'2 Analysis-Calculated (percent): C, 42.85; H, 2.40; N, 16.66; S, 9.53.Found (percent): C, 42.87; H, 2.37; N, 16.58; S, 9.45. I

Infra-red spectrum:

EXAMPLE 12 I H N [2-thenoyl) Nor .(i) leucyl] -N [5 "-nitro-2"-furylacrylidene] -hydrazine 66 g. (mol)/2 of Nor (i) leucine aresuspended'in 375 ml. of absolute ethanol. Hydrochloric acid gas isintroduced into the mixture at boiling point for 6 hours (untilsaturation is reached). The substance is evaporated to dryness and thenthe treatment is repeated with fresh ethanol. After again beingevaporated to dryness, the crude hydrochloride is treated withchloroform, saturated with N11 By distillation, there are obtained 38.7g. of a colourless liquid of B.P. =102-103 C.; after redistillation B.P.=98-99 C. V.P.C.=100%.

Analysis.Calculatedv (percent): C, 60.34; H, 10.76; N, 8.80. Found(percent): C, 60.30; H, 10.80; N, 8.75.

" NHz, woo-3,400 cm. 00, 1,740 cm.

(b) (N-2-theonyl)-Nor leucine ethyl ester:

on. OrzHwNO S 1T 1 CONH- H-CO on s 2 2 M=269.34

15.9 g. (mol/ 10) of Nor (i) leucine ethyl ester are dissolved in 50 m1.of pyridine, whereafter there are introduced 14.7 g. (mol/ 10:14.65 g.)of Z-thiophene carboxylic acid chloride. The mixture is left for onehour at ambient temperature and then it is poured into iced water. Theoil which forms quickly crystallises. There are obtained 24 g. of alight yellow product with'a melting point of 81 C., with a yield of80.7% (theoretical yield=26.9 g.). After recrystallisation (ethylacetate), the melting point is 81-82 C.

Analysis.Ca1culated (percent): C, 57.97; H, 7.11; N, 5.20; S, 11.90.Found (percent): C, 57.91; 'H, 7.12; N, 5.21; S, 12.01.

13 (c) N -[(2-theony1) Nor 1eucy1]-hydrazide:

13.5 g. (mol/20=13.45 g.) of N -2-thenoy1N0r-(i) leucine ethyl ester, 20ml. of isopropanol, 10.2 g. (mo1/5==10 g.) of NH -NHg-98% H and 0.5 ml.of acetic acid are heated under reflux for hours. The crude mixture withaddition of ether yields 11.5 g. of white crystals with a melting pointof 116-118 C. Yield=90% theoretical yield=12.8 g.). Afterrecrystallisation (isopropanol), the melting point is 127-128 C.

Analysis.-Calculated (percent): C, 51.75; H, 6.71; N, 16.46; S, 12.96.Found (percent): C, 51.77; H, 6.69; N, 16.47; S, 12.54.

'yNH, 3,300 cm.- (a single peak) CO (conjugated), 1,640 cmr CO, 1,670cm.-

(d) N -[(2'-thenoyl)-Nor-( 1eucyl]-N -[5"-nit1'o-2"-furyl-acrylidene]-hydrazine: 8.5 g. (mol/30) of N -[(2'- thenoyD-NOr-(leucy1]-hydrazide in 180 ml. of methanol and 5.6 g. (mol/ 30) of5-nitro-2-furyl acrolein in 56 ml. of tetrahydrofuran are heated underreflux for 2 hours. After concentration to half volume, there areobtained, in two outs: 7.7 g. of product of melting point 188-192" C.,yield=57.5% (theoretical yield=13.4 g.).

After being recrystallised twice (ethyl acetate), the melting point is200201 C. (with decomposition).

Analysis.Calculated (percent): C, 53.46; H, 4.98; N, 13.86; S, 7.92.Found (percent): C, 53.44; H, 5.01; N, 13.79; S, 7.86.

Infra-red spectrum:

'yNH, 3,300 cm.- 'yCO (conjugated), 1,640 cm. 1,680 cm.

EXAMPLE 13 -Zn-NHooo GHQ At 70 C. 11 g. (mol/30==10.97 g.) of (N-Cbotyrosyl)-hydrazide are dissolved in 180 m1. of ethylene glycol and then5.6 g. (mol/ 30) of 5-nitro-2-furyl acrolein in 56 ml. oftetrahydrofuran are introduced at a temperature of 60 C. Heating takesplace for 2 hours at 60 C. and then water is added until a clouding isformed. There is obtained an impure yellow solid, which is separated byfiltering with suction. 16.3 g. of product (theoretical yield=16.1 g.)are obtained with a melting point of 123-125 C. After recrystallisationfrom 150 ml. of methanol, a product with a melting point of 182183 C. isobtained in a yield of 9.1 g. =56.5% (theoretical yield=16.1 g.).

After a second recrystallisation from methanol, the melting point is184185 C.

Analysis.Calculated (percent): C, 60.24; H, 4.64; N, 11.70. Found(percent): C, 60.20; H, 4.63; N, 11.66.

7011, 3,6003,400 cmr (large) C0 (amide) =1,690 cm.- 00 =1,740 cmr 0Nol=1,520-1,550 cmr (Cbo) L (0 =0), 1,015-1,075 cm' EXAMPLE 14 Between 0and +5 C., 23.2 g. (mol/10=23.16 g.) of a hydrochloride of tyrosinemethyl ester are dissolved in 100 ml. of water which contain 33.5 g.(mol/ 10) of NaHCO While stirring, there are simultaneously added: 13 g.(mol/ 10) of furoyl chloride and 8.5 g. (mo1/10) of NaHCO in ml. ofwater. Heating takes place at 50 C. for one hour, the product isagglomerated and it solidifies when the heating is terminated. Afterfiltering with suction and washing with water, there are obtained 24.6g. of a slightly coloured product which has a melting point of 117-119C., the yield being 85.4% (theoretical yield 28.9 g.). Afterrecrystallisation (ethyl acetate+traces of hexane), the melting point israised to 123-125 C.

Analysis.Calculated (percent): C, 62.29; H, 5.22; N, 4.84. Found(percent): C, 62.24; H, 5.20; N, 4.77.

vOH 3 6803,400 emr (l arge) 745 cmr L I I 0/ O (ester), 1,740 cm.- 880em.-

(b) N -[N'-2'-furoyl (1:) tyrosyl]-hydrazide:

C uHrsNsO 4 H M =289. 28 The following are left at ambient temperaturefor 48 hours: 14.5- g. (mol/20) of N-furoyl (i) tyrosine methyl ester in220 ml. of alcohol (to be made tepid for dissolving purposes), 10.2 g.(mol/5=10 g.) of

NH2NH2'98% H20 and 0.5 ml. of acetic acid. Crystallisation occurs and,after being left for a short time in the refrigerator and adding 15ether, there are obtained by suction-filtering 10.2 g. of white product,yield=70.6% (theoretical yield=14.45 g.), with a melting point of174-l75 C. After recrystallisation from ethanol, the melting point is1755-176 C.

Analysis.-Calculated (percent): C, 58.12; H, 5.22; N, 14.52. Found(percent): C, 58.10; H, 5.30; N, 14.48.

'yOH, 3,600-3,400 cm.- NH, 3,300 cm. CO (conjugated), 1,650 cm.-

(c) N -[N'-2-furoy1 (i) tyrosyl]-N -[5"-nitro-2"-furylacrylidene]-hydrazine: At the temperature of 60 C., 14.5 g.(mol/20) of N -[N-2'-furoyl (i) tyrosyl]-hydrazide are dissolved in 320ml. of ethylene glycol. At a temperature lower than 60 C., 8.4 g.(mol/20) of 5- nitro-2fury1 acrolein in 84 ml. of tetrahydrofuran areintroduced thereinto. After heating at 80 C. for 4 hours, thetetrahydrofuran is evaporated under vacuum.

By filtering with suction (diflicult) and after washing with water, ayellow solid is separated which has a melting point of 192194 C. Afterrecrystallisation (Waterdimethyl-formamide 1:1), M.P.=229230 C., yield:12.4 g.=57% (theoretical yield=21.6 g.).

Analysis.Calculated (percent): C, 57.55; H, 4.13; N, 12.77. Found(percent): C, 57.53; H, 4.14; N, 12.79.

110E, 3,540 cm.- (sharp) NH 3,300 cm.

C O 1,680 cm.- 0 0 (conjugated), 1,650 cm.'

1,020 em.- 1,080 cmr 750 cm.-

EXAMPLE 15 N [N'- 5 -nitro-2'-thenoyl i phenylalanyl] -N[5'-nitro-2"-furylacrylidene] -hydrazine (a) N-[5'-nitro-2'-thenoyl]phenyl alanine ethyl ester:

NOUCONH-(FH-COzCzHB S CH,

19.3 g. (mol/ 10) of (i) phenyl alanine ethyl ester are dissolved in 150ml. of pyridine. 19.2 g. (mol/ 10 =19.15 g.) of 5-nitro-2-thenoylchloride are added in small portions. After stirring at ambienttemperature for one hour, cooling in iced water, filtering with suctionand washing with water, there are isolated 29 g. of a product having amelting point of 150-151 C., with a yield of 83.5% (theoreticalyield=34.8 g.).

After recrystallisation from ethanol, the melting point is 150-151 C.

Analysis.--Calculated (percent): C, 55.16; H, 4.63; N, 8.04; S, 9.20.Found (percent): C, 55.18; H, 4.59; N, 8.02; S, 9.22.

'yNH, 3,300 cm.-

C-NO 1,560 cm.-

CO (ester), 1,7401,750 cm. (split up) CO (conjugated amide), 1,630 cm.-

1 6 (b) N [N'- (5 '-nitro-2'-thenoyl) (i) phenylalanylhydrazide:

l i C14H14N O4S NO 8 C ONH-CH-CONH-NHz Ha M=334.34

20.8 g. (mol)/ 16.7 of N -[N'-(5-nitro-2'-thenoyl) (i) phenyl alanineethyl ester are dissolved in ml. of tetrahydrofuran and 175 ml. ofmethanol. 9.2 g. (mol/ 5.55 =9 g.) of 98% hydrazine hydrate in solutionin 30 ml. of methanol are then introduced slowly at ambient temperature(in about 1 hour). The substance is left at ambient temperature for 48hours and is then heated under reflux for 1 hour. After concentration tohalf volume, followed by adding ether, there is isolated a first cut of11 g. of yellow product of melting point 190192 C. and a second cut of3.4 g. of yellow product of melting point=l80- C. Afterrecrystallisation of the 14.4 g. from 650 ml. of ethanol, 8 g.,yield=40% (theoretical yield=20 g.) of yellow product of M.P. =206208 C.are obtained, and following a second recrystallisation from ethanol, themelting point is 214-216 C.

Analysis.Calculated (percent): C, 50.29; H, 4.20; N, 16.76; S, 9.61.Found (percent): C, 50.27; H, 4.18; N, 16.79; S, 9.64.

(c) N -[N'-(5-nitro-2'-thenoyl) phenylalanyl]- N-[5"-nitro-2"-furylacrylidene]-hydrazine: 10.1 g. (mol/ 335 of N-[N-(5-nitro-2-thenoyl) (i) phenylalanyl]- hydrazine are dissolved atboiling point in 280 ml. of tetrahydrofuman. 4.9 g. (mol/ 33) of5-nitro-2-furyl acrolein in 49 ml. of tetrahydrofuran are added dropwisethereto.

After heating for 2 hours under reflux, evaporation to dryness iseffected and then ether is recovered. There are isolated 13 g. of yellowproduct having a melting point of 131-133 C. with a yield of 89%(theoretical yield 14.6 g.). After recrystallisation (ethanol-dimethylformamide 1:1 and traces of water), the melting point becomes 215-222"C.

Analysis.Calculated (percent): C, 52.18; H, 3.54; N, 14.49; S, 6.63.Found (percent): C, 52.20; H, 3.57; N, 14.50; S, 6.62.

vNH, 3,280 cm.-

CO, 1,680 cm.-

CO (conjugated), 1,630 cm.- CNO 1,540-1,550 cm.

EXAMPLE 16 N (5'-nitro-2-furylacrylidene) ]-N [N'-5"-nitro-2"- thenoyl)(i) serylJ-hydrazine (a) N-(5'-nitro-2'-thenoyl) serine ethyl ester:

Nozi CONHCHCO C H s l 2 2 5 CHQOH ioHizNz o M=288. 28

CO, 1,730 cm.- O-N 02, 1,540 cmr (b) N -[5'-nitro-2'-thenoyl (i)seryl]-hydrazide:

14.4 g. (mol) 20 of N (5'-nitro-2'-thenoyl) (i) serine ethyl ester aredissolved in 200 ml. of methanol. At a temperature of 5 C., 7.7 g.(mol/6.66=7.5 g.) of NH NH -98% H O in 24 ml. of methanol are veryslowly added.

After the addition, the mixture is cooled to C. and stirring iscontinued for 2 hours. The mixture is left at ambient temperature for 48hours. After filtering with suction and washing with ether, there areisolated 13.1 g.=95.6% (theoretical yield=13.7 g.) of a product meltingat 189 C. After recrystallisation from water, the melting point is 190C. (with decomposition).

Analysis.Calculated (percent): C, 35.03; H, 3.67; N, 20.47; S, 11.69.Found (percent): C, 35.05; H, 3.69; N, 20.50; S, 11.79.

'yOH, 3,6003,400 cm.

NH, 3,300 Cm."

CO, 1,670 cm.-

CO (conjugated), 1,640 cm.

(0) 'N -[('-nitro 2' furylacrylidene) N (N-5"- nitro- "-thenoyl) (i)seryl]-hydrazine: 9.2 g. (mol/30) of N -[5'-nitro 2' thenoyl (i)scrylJ-hydrazide are dissolved at 60 C. in 210 ml. of ethylene glycol.5.6 g. (mol/30=5.56 g.) of 5-nitro 2 furylacrolein in 56 ml. oftetrahydrofuran are added to the solution. After heating for 2 hours at60 C., the tetrahydrofuran is driven 011 under vacuum and water is addedto the residue. 12.1 g. of product crystallises, this product melting at217 C. with decomposition. Yield=85% (theoretical yield=14.l g.). Afterrecrystallisation from ethyl acetate-dimethyl formamide (2:1), themelting point is 217 C. (with decomposition) Analysis.Calculated(percent): C, 42.56; H, 3.09; N, 16.55; S, 7.57. Found (percent): C,42.58; H, 3.13; N, 16.50; S, 7.60.

0H, 3,520 cm.

NH, 3,320 cm.

CO, 1,700 cm? CO, 1,650 cm.- (conjugated) C=N, 1,630 cmr CNO 1,540 cm.-

What we claim is: 1. A substituted (nitrofuryl acrylidene) hydrazinerepresented by the formula:

in which n=1 or 0; G is a member of the group consisting of thenoyl,nitrothenoyl and carbobenzoxy radicals; and R, when n=1 is a member ofthe group consisting of hydrogen and methyl, butyl, isobutyl,6-(2-furoyl)aminobutyl, benzyl, hydroxymethyl and p-hydroxybenzylradicals.

2. N [N-2'-furoyl (i) alanyl]-N -[5"-nitro-2-furylacrylidene1-hydrazinein accordance with claim 1.

3. N -[N'-carbobenzoxyglycyl] N [5 nitro-2'-furylacrylidene1-hydrazinein accordance with claim 1.

4. N -[N-2-thenoylglycyl] N [5-nitro-2"-furylacrylidene1-hydrazine inaccordance with claim 1.

5. N -[2'-thenoyl] N [5"-nitro-2"-furylacrylidene]- hydrazine inaccordance with claim 1.

6. N -[N-(2-thenoyl) (i) leucyl] N [5"-nitro-2"-furylacrylidene]-hydrazine in accordance with claim 1.

7. N -[(2'-thenoyl) N or (i) leucyl] N [5"-nitro2"-furylacrylidene]-hydrazine in accordance with claim 1.

8. N -[5-nitro 2' furylacrylidene]-N (N"-carbobenzoxy tyrosyl]-hydrazinein accordance with claim 1.

9. A hydrazine in accordance with claim 1 selected from the groupconsisting of [N -(5'-nitr0 2' thenoyl)- 'N -(5"-nitro 2" furylacrylidene)] hydrazine and [N -(5-nitro 2' thenoyl glycyl) N-(5"-nitro-2"-furyl acrylidene) ]-hydrazine.

10. [N -(5 nitro 2' thenoyl) N (5"-nitro-2"- furyl-acrylidene)]hydrazine in accordance with claim 9.

11. [N (5' nitro 2 thenoyl glycyl) N (5"- nitro 2" furylacrylidene)]-hydrazine in accordance with claim 9.

12. A hydrazine in accordance with claim 1 wherein G is a nitrothenoylor carbobenzoxy radical.

13. A substituted (nitrofuryl acrylidene) hydrazine represented by theformula:

in which G is a member of the group consisting of furoyl, thenoyl,nitrothenoyl and carbobenzoxy radicals; and R is a member of the groupconsisting of hydrogen, methyl, butyl, isobutyl, 6-(2-furoyl)aminobutyl, benzyl, hydroxymethyl and p-hydroxybenzyl radicals.

14. A hydrazine in accordance with claim 1, wherein n=0.

REFERENCES CIT=ED Stradins et al.: Latviajas PSR Zinatnu Akad. Vestis,1958, No. 1, pp. 113-20.

Saikachi et al.: Chemical Abstracts, vol. 50, cols. 9371- 9372 (1956).

Ivanov et al.: Chemical Abstracts, vol. 52, col. 12837 8).

Toda et al.: Chemical Abstracts, vol. 52, cols. 20388- 20389 (1958).

Uota et al.: (1957).

Stradins et al.: Chemical Abstracts, vol. 54, col. 20085 (1960).

Chemical Abstracts, vol. 51, col. 5846 JOHN D. RANDOLPH, PrimaryExaminer U.S. Cl. X.R.

260240.1, 332.2 C, 347.3, 347.4, 471 C, 482 C; 424- 275, 285

G UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.,847,911 Dated November 12, 1974 Q Inventods) Etienne SZARVASI et al.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below: Col. 1,line 69 after "1," insert --is--; same line, after "hydrogen," insert--a-,

Col. '5, line 74. delete formula and insert therefor C1H.N|OzS QLLCONII-CIh-CQNH-NH:

S M=199.H

Col. 6, line 20 delete "-thenoylglycol" and insert therefor--thenoylglycyl-. Q

Col. 7 line 15, delete "70" after "9.84".

Col. 8, line 26, delete"NaNCO and insert --NaHCO line 37, after "(large"insert a line 46, delete C H N O" and insert l zo a Col. ll, line 24,delete "H=402.45" and insert O line 50, to the right of the formulainsert' -C H NO S B M 20l.l8-;

Patent No. 3:847 911 Dated November 12, 1974 Q Inventor(s) EtienneSZARVASI et al. Page 2 It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

6 Col. ll, line 65, delete "N and insert --N Col. 12, line 14 delete"2-thnoyl)"and insert --(2'thenoyl)--;

. Col. 16, line 34, delete "335" and insert --33- Signed and Scaled thisnineteenth Day of A w Q [SEAL] Alte'St:

RUTH C. MASON C. MARSHALL DANN Alresll'ng Officer (mnmissimzer oj'Palemsand Trademarks

1. A SUBSTITUTED (NITROFURYL ACRYLIDENE) HYDRAZINE REPRESENTED BY THEFORMULA: